The goal of the study was to investigate the association between circulating cholesterol levels and early-onset Alzheimer's disease (EOAD), and to identify genetic variants underlying a possible association.

Questions Addressed:

How close is the association between cholesterol levels and early-onset AD?

What type of cholesterol is linked to early-onset AD?

What genetic variants are associated with early-onset AD?

How does this research add to what is generally known about AD?

Study Synopsis and Perspective:

Action Points

Elevated LDL cholesterol levels were tied to a higher probability of early-onset Alzheimer's disease (AD), as were total cholesterol, and apolipoprotein B (Apo B) levels, even after adjusting for the apolipoprotein E ε4 (APOE E4) allele

These data do not show a causal link between AD and cholesterol, which will require more research, but if researchers can prove such a link exists, it may be necessary to revise targets for LDL cholesterol to help reduce Alzheimer's risk.

Elevated LDL cholesterol levels were tied to a higher probability of early-onset AD, a case series showed.

Early-onset Alzheimer's patients had higher levels of LDL cholesterol, total cholesterol, and apolipoprotein B (Apo B) levels, even after adjusting for the apolipoprotein E ε4 (APOE E4) allele -- a genetic risk factor known to raise circulating cholesterol, reported Thomas Wingo, MD, of Emory University in Atlanta, and colleagues.

Moreover, early-onset Alzheimer's cases were strongly associated with rare variants of APOB, which codes for the major protein of LDL cholesterol, they wrote in JAMA Neurology.

"A big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer's risk," Wingo told MedPage Today. "The existing data is murky on this point."

Early-onset Alzheimer's occurs before age 65, and has a large genetic basis, with heritability of 91% to 100%. Mutations in three genes that cause Alzheimer's -- amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) -- were discovered in families with early-onset disease, but most likely account for <10% of incident cases.

With this in mind, Wingo and colleagues set out to examine three potential causes of early-onset Alzheimer's: Alzheimer's genetic variants, circulating plasma lipoproteins, and APOB, the latter known to harbor rare variants with strong effects on raising or lowering LDL cholesterol.

To collect data, they sequenced APOB, APP, PSEN1, and PSEN2 in samples from 2,125 early-onset cases and controls recruited from 29 Alzheimer's disease research centers from 1984 through 2015. They also measured plasma cholesterol levels in 267 frozen samples collected from early-onset Alzheimer's patients, and controls from 2009 to 2014 at Emory University and the University of California San Francisco Alzheimer's research centers.

Of the 2,125 samples that underwent genetic sequencing, 1,276 were from women (60.0%), and 654 (30.8%) were from patients with early-onset Alzheimer's. The average age of early-onset patients was 55.6, and the average age of controls was 72.

In the latter group, only 3.4% carried APP, PSEN1, and PSEN2. The APOE E4 allele accounted for 10.1% of the variance.

The findings generate a number of questions, including whether APOB has both protective and deleterious variants, and what role APOB variants may play in late-onset Alzheimer's disease, noted Wingo and colleagues.

While this study could not prove causality, "both APOB and APOE act on plasma circulating cholesterol, suggesting a connection, perhaps through effects on brain vasculature," the researchers hypothesized. "Moreover, APOE is a key gene in brain homeostasis, whereas APOB is not expressed in the brain. Thus, variants in APOE that alter cholesterol metabolism may act both centrally and peripherally, whereas APOB variants may act predominantly if not exclusively through the periphery."

"Our study provides evidence that circulating cholesterol is associated with EOAD independently of APOE E4. Furthermore, we have identified novel rare genetic coding changes in APOB that are associated with EOAD independently of APOE," they wrote.

The APOB variants the researchers found do not fully explain the association between high levels of LDL cholesterol and EOAD, which calls for more additional studies to locate more genetic variants which underlie the connection between lipid metabolism and Alzheimer's disease pathogenesis, they concluded.

Study limitations included the fact that, because of the rarities of the alleles tested, they could not be analyzed using Mendelian randomization. Cholesterol data may also be confounded by Alzheimer's severity, smoking, or cholesterol-lowering drugs, however the genetic link between APOB and early-onset Alzheimer's is unlikely to be affected by these variables, the authors added.

This study investigated the link between circulating cholesterol levels and early-onset AD, and the underlying genetic mechanisms. Researchers first found a strong association between elevated LDL levels and EOAD that was only partially mediated by APO E4. Ultimately, they discovered a significant association between rare coding variants in APOB and early-onset AD independently of APOE E4.

Because the APOB variants found do not fully account for the association between elevated LDL cholesterol levels and early-onset AD, additional studies must be conducted to further clarify the contribution of lipid metabolism to AD pathogenesis, the authors concluded.

"These results collectively confirm that these four genes account for only a minority of the strong genetic predisposition seen in early onset Alzheimer's disease, and additional genes are likely to be involved," noted Makoto Ishii, MD, PhD, of Weill Cornell Medicine in New York City, in an accompanying editorial.

"Overall, this is an important study that provides the first evidence that rare genetic coding variants of APOB are strongly associated with early-onset Alzheimer's disease," the editorialist observed. Consistent with these findings, a transgenic mouse model overexpressingAPOB had significant memory impairment and increased beta-amyloid levels compared with wild-type mice, he noted.

The findings generate a number of questions, including whether APOB has protective and deleterious variants and what role APOB variants may play in late-onset Alzheimer's disease, noted Wingo and colleagues.

"Our current work is focused on testing whether there is a causal link," Wingo stated. "If there is a causal link between Alzheimer's disease and cholesterol, we might need to revise targets for LDL cholesterol to help reduce Alzheimer's risk."

"However, previous studies measuring circulating apolipoprotein B levels in humans have been inconclusive, with a large population study finding no association between circulating apolipoprotein B levels and incident dementia or Alzheimer's disease," he said. "Therefore, whether these findings can be verified in individuals with late-onset Alzheimer's disease remains to be determined."

The study suggests other contributing factors as well -- possibly rare variants in other genes involved directly in LDL cholesterol metabolism -- may be involved, Ishii added. And while this analysis focused on cholesterol, "similar studies investigating other cerebrovascular risk factors, such as insulin resistance, or type 2 diabetes mellitus in individuals with early-onset Alzheimer's disease, may be equally enlightening," he wrote.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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